Code to avoid flip-flop kinetics

Dear NMUsers, having to deal with the flip-flop kinetics phenomenon, I had a look at previous posts on the NMusers list. I found this post particularly enlightening: http://www.cognigencorp.com/nonmem/nm/99aug072003.html Some code was proposed to avoid the flip-flop at population and individual level. Here's a not-so-brief summary. This parameterization solves the issue at population level: CL=THETA(1)*EXP(ETA(1)) V=THETA(2)*EXP(ETA(2)) TVKE=THETA(1)/THETA(2) TVKA=TVKE+THETA(3) KA=TVKA*EXP(ETA(3)) However, it does not prevent the phenomenon occurring at individual level. Vlamidir Piotrovsky proposed the code below, which does solve the problem at individual level, but makes the interpretation of the results a bit awkward and introduces correlation among the model parameters. In particular, variance of ETA3 was greatly increased. CL=THETA(1)*EXP(ETA(1)) V=THETA(2)*EXP(ETA(2)) KE=CL/V KA=KE+THETA(3)*EXP(ETA(3)) Another approach, suggested by Nick Holford, implements error recovery using EXIT 1. The code is reported below: CL=THETA(cl)*EXP(ETA(cl)) V=THETA(v)*EXP(ETA(v)) KA=THETA(ka)*EXP(ETA(ka)) K=CL/V IF (KA.LE.K) EXIT 1 101 ; try again (PREDERR message error code 101) As far as I understand, this interrupts the computation whenever the flip-flop occurs and lets NONMEM restart. However, if such an error arises at initialization, NONMEM does not recover and the run goes no further. Nick probably experienced something similar, but apparently received no answer http://www.cognigencorp.com/nonmem/nm/99oct072004.html Does anyone know of a way around this drawback? Or have other code to deal with flip-flop kinetics? Thank you in advance, Paolo -- ------------------------------------------------ Paolo Denti, Post-Doctoral Fellow Division of Clinical Pharmacology Department of Medicine University of Cape Town K45 Old Main Building Groote Schuur Hospital Observatory, Cape Town 7925 South Africa phone: +27 21 404 7719 fax: +27 21 448 1989 email: [email protected]